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Serotonin and central nervous system fatigue: nutritional
1,2
considerations
J Mark Davis, Nathan L Alderson, and Ralph S Welsh
ABSTRACT Fatigue from voluntary muscular effort is a cular junction (3). Strategies designed to offset peripheral fatigue
complex phenomenon involving the central nervous system and enhance physical (athletic) performance most often involve
(CNS) and muscle. An understanding of the mechanisms within alterations in training and nutrition (4). However, very little is
muscle that cause fatigue has led to the development of nutri- known about these issues regarding central fatigue.
tional strategies to enhance performance. Until recently, little Both types of fatigue (peripheral and central) can potentially
was known about CNS mechanisms of fatigue, even though the occur in individuals at rest and during vigorous exercise. With Downloaded from
inability or unwillingness to generate and maintain central acti- individuals in a rested state or performing low-intensity daily
vation of muscle is the most likely explanation of fatigue for activities, peripheral fatigue is less likely to occur because fuel
most people during normal daily activities. A possible role of is readily available and acidosis within the muscle is low. CNS
nutrition in central fatigue is receiving more attention with the mechanisms are more likely to promote fatigue experienced dur-
development of theories that provide a clue to its biological ing normal daily activities. Furthermore, feelings of fatigue are a
mechanisms. The focus is on the neurotransmitter serotonin common feature in situations such as postoperative recovery, jet ajcn.nutrition.org
[5-hydroxytryptamine (5-HT)] because of its role in depres- lag, sleep deprivation, post-meal drowsiness, and chronic fatigue
sion, sensory perception, sleepiness, and mood. Nutritional syndrome,all of which do not apparently involve muscle defects.
strategies have been designed to alter the metabolism of brain Because the mechanisms of fatigue in these situations are not
5-HT by affecting the availability of its amino acid precursor. well understood, it is often thought that nothing can be done to
Increases in brain 5-HT concentration and overall activity have alleviate their effects. by guest on October 3, 2012
been associated with increased physical and perhaps mental Investigators, however, have now begun to focus more heavily
fatigue during endurance exercise. Carbohydrate (CHO) or on possible mechanisms of fatigue involving the CNS. The most
branched-chain amino acid (BCAA) feedings may attenuate direct evidence of central fatigue has been generated through the
increases in 5-HT and improve performance. However, it is dif- use of a new analytic technique, transcranial magnetic stimula-
ficult to distinguish between the effects of CHO on the brain tion. With this technique, magnetically generated stimulation of
and those on the muscles themselves, and most studies involv- the motor cortex elicits an action potential to the alpha motor
ing BCAA show no performance benefits. It appears that neuron of the spinal column and, in turn, to the neuromuscular
important relations exist between brain 5-HT and central junction. Direct evidence of inhibition of central drive after exer-
fatigue. Good theoretical rationale and data exist to support a cise is now available (5–7). Previously, evidence of central
beneficial role of CHO and BCAA on brain 5-HT and central fatigue was commonly acknowledged only by default when there
fatigue, but the strength of evidence is presently weak. was no evidence of specific muscle impairment.
Am J Clin Nutr 2000;72(suppl):573S–8S. It has long been known that nutritional status can alter brain
neurochemistry [especially that involving carbohydrates and the
KEY WORDS Central fatigue, nutrition, prolonged exer- neurotransmitter serotonin, or hydroxytryptamine (5-HT)], in
cise, carbohydrates, branched-chain amino acids, serotonin, conjunction with various psychologic and other disorders,
dopamine, tryptophan including depression, premenstrual syndrome, sleepiness, impaired
perceptual and cognitive function, and seasonal affective disor-
der, all of which include fatigue as a common symptom (8–10).
INTRODUCTION It is therefore tempting to suggest a possible role of nutrition in
Research in the area of fatigue has focused primarily on central fatigue that is evoked by exercise. However, during exer-
peripheral fatigue, which involves reductions in the ability of cise, many of the variables thought to regulate an effect of nutri-
muscle to perform work because of impairments anywhere along
the chain of command from neuromuscular transmission to actin- 1From the Department of Exercise Science, School of Public Health, Uni-
myosin cross-bridging (1, 2). However, the stimulus for muscular versity of South Carolina, Columbia, SC
contraction is initiated in the brain, and therefore central fatigue 2Address reprint requests to JM Davis, Department of Exercise Science,
may occur if alterations within the central nervous system (CNS) University of South Carolina, Blatt Center, Wheat Street, Columbia, SC
decrease the ability to voluntarily send a signal to the neuromus- 29208.
Am J Clin Nutr 2000;72(suppl):573S–8S. Printed in USA. © 2000 American Society for Clinical Nutrition 573S
574S DAVIS ET AL
circulates loosely bound to albumin; however, unbound, or free,
TRP (f-TRP) is transported across the blood-brain barrier. This
transport occurs via specific receptors that TRP shares with other
large neutral amino acids, most notably the branched-chain
amino acids (BCAAs) leucine, isoleucine, and valine. Thus, 5-
HT synthesis in the brain increases when there is an increase in
the ratio of the f-TRP concentration in blood plasma to the total
BCAA concentration in plasma (ie, when f-TRP:BCAA rises).
This increase was proposed to occur during prolonged exercise
for 2 reasons. First, BCAAs are taken up from blood and oxi-
dized for energy during contraction of skeletal muscles. Second,
fatty acid (FA) concentrations in plasma increase, causing a par-
allel increase in plasma f-TRP because FAs displace TRP from
its binding sites on albumin (Figure 1).
Physical exercise is not the only condition under which
changes in TRP uptake and 5-HT metabolism in the brain have
been linked to altered behavior. Although TRP uptake in the
brain is rather stable under many conditions (12), immobilization
stress or ingestion of a high-carbohydrate (CHO) meal can
increase uptake. TRP uptake also appears to be elevated in
elderly persons and in persons with depression, various appetite Downloaded from
disorders, liver failure, and renal disease (8). However, the
mechanism for increased brain TRP uptake is often different
under various conditions. For example, immobilization stress
appears to increase TRP uptake by enhancing the kinetics of
TRP (and other amino acid) transport to the brain (13). A high-
CHO meal stimulated brain TRP uptake via an insulin-induced ajcn.nutrition.org
decrease in the plasma concentration of competing large neutral
amino acids and FAs (14–15). A combination of these mecha-
FIGURE1.Primary components of the central fatigue hypothesis at nisms may occur with aging (16). Moreover, the mechanism of
rest and during prolonged exercise. BCAA, branched-chain amino acid; TRP uptake may depend on the specific situation in which treat-
FA, fatty acid; f-TRP, free tryptophan; 5-HT, 5-hydroxytryptamine ment is administered. For example, CHO ingestion has opposite
(serotonin); TRP, tryptophan. effects on brain TRP uptake depending on whether the subject is by guest on October 3, 2012
at rest or doing vigorous exercise. At rest, brain TRP uptake is
tion on brain 5-HT do not respond in the same fashion as they accelerated because of an insulin-induced decrease in plasma
would under resting conditions (discussed further in a later sec- concentration of competing large neutral amino acids and FAs.
tion of this paper). This phenomenon, along with the lack of During vigorous exercise, however, insulin release is inhibited
good techniques to distinguish between central and peripheral and brain TRP uptake is attenuated because of reductions in FA
fatigue during exercise has severely limited scientific study in mobilization and plasma FA and f-TRP concentrations (17, 18).
this area (3). Nevertheless, there are now intriguing theories and
some evidence to support a possible role of nutrition in central
fatigue. This review focuses primarily on current research on BRAIN 5-HT AND CENTRAL FATIGUE DURING
possible nutritional strategies that may influence brain 5-HT and EXERCISE
central fatigue during exercise. Studies in both rats and humans provide good evidence that
brain 5-HT activity increases during prolonged exercise and that
this response is associated with fatigue. Investigators are only
THE CENTRAL FATIGUE HYPOTHESIS beginning to explore the possible physiologic mechanisms
Evidence is accumulating in support of a role for the neuro- behind this response.
transmitter 5-HT, and perhaps dopamine, in central fatigue dur- The serotonergic system is associated with numerous brain
ing prolonged exercise. Newsholme et al (11) were the first to functions that can positively or negatively affect endurance per-
form the hypothesis that, because of its well-known effects on formance. We have observed that fatigue during prolonged exer-
arousal, lethargy, sleepiness, and mood, 5-HT may have a role as cise in rats is associated with increased 5-HT and reduced
a possible mediator of central fatigue. It was also hypothesized dopamine concentrations in the brain (19). Other evidence has
that exercise could influence important factors that control the shown an inverse relationship between 5-HT and dopamine in cer-
synthesis and turnover of 5-HT in the brain. This hypothesis sug- tain brain areas. On the basis of these findings, it is our working
gested that increased amounts of brain 5-HT could lead to cen- hypothesis that a low ratio of brain 5-HT to dopamine favors
tral fatigue during prolonged exercise, thus affecting sport and improved performance (ie, increased arousal, motivation, and
exercise performance. optimal neuromuscular coordination), whereas a high ratio of 5-
Increased synthesis of 5-HT in the brain occurs in response to HT to dopamine favors decreased performance (ie, decreased moti-
an increase in the delivery of blood-borne tryptophan (TRP), an vation, lethargy, tiredness, and loss of motor coordination) (3).
amino acid precursor to 5-HT. Most of the TRP in blood plasma The latter would constitute central fatigue.
NUTRITION AND CENTRAL FATIGUE 575S
Chaouloff et al (20–22) were the first to demonstrate an effect agonists but increased after the administration of a 5-HT antag-
of treadmill exercise on the ratio of f-TRP to BCAA in plasma, onist (27). These modulations in run time to fatigue occurred
as well as on the concentrations of 5-HT and its primary metabo- despite no apparent alterations in body temperature, blood glu-
lite 5-hydroxyindole acetic acid (5-HIAA) in the brain. Chaouloff cose, muscle and liver glycogen, or various stress hormones (27).
et al (21, 22) initially showed that the total concentration of TRP Similar studies were conducted with human subjects in which
in plasma was unaffected in rats after 1–2 h of treadmill running brain 5-HT activity was increased by the administration of either
(20 m/min). However, the concentration of f-TRP in plasma was of the 5-HT agonists paroxetine (28) or fluoxetine (29). Fatigue
markedly increased and was accompanied by an increase in TRP occurred earlier during running or cycling, and ratings of per-
and 5-HIAA concentrations in the brain. Similar changes were ceived exertion were higher when the drugs were administered
found in cerebrospinal fluid, and concentrations returned to than when a placebo was administered. As in the animal studies,
basal amounts by 1 h after exercise (23). The same authors (24) there were no obvious differences in cardiovascular, thermoreg-
also found that endurance-trained rats that had undergone ulatory, or metabolic function that could explain the differences
repeated sessions of prolonged exercise showed increased in exercise time to fatigue.
turnover of plasma FA, brain TRP, and brain 5-HT immediately
after exercise, but that this increase was smaller than that found
in less well-trained rats. This was the first evidence that NUTRITION,5-HT,AND CENTRAL FATIGUE DURING
endurance running is associated with an increase in 5-HT pro- EXERCISE
duction and turnover, which in turn is due to an increase in One of the implications of the central fatigue hypothesis is that
plasma f-TRP. nutritional manipulations can alter brain neurochemistry and
We began to look more carefully at the possible relationship exercise performance. Two main areas of focus involve BCAA
between elevated 5-HT concentrations in the brain and fatigue. and CHO supplementation. Intake of BCAA should lower the Downloaded from
One experiment was designed to study the time course of plasma f-TRP-to-BCAA ratio and presumably 5-HT synthesis,
changes in brain neurotransmitters during exercise to fatigue owing to decreased f-TRP transport across the blood-brain bar-
(19). Rats were killed at points corresponding to rest, after 1 h of rier. As BCAAs compete with f-TRP for the same transport sites
treadmill running (1 h) and at fatigue (approximately 3 h). The across the blood-brain barrier, a reduction of this ratio will, in
treadmill speed (20 m/min) and grade (5%) were set to elicit turn, decrease the amount of f-TRP entering the brain, thereby
·
60–65% of VO2max. The midbrain, striatum, hypothalamus, limiting 5-HT synthesis (30). The postulated benefits of CHO ajcn.nutrition.org
and hippocampus were analyzed for concentrations of 5-HT and feedings in limiting central fatigue are based on the fact that the
dopamine and their primary metabolites, 5-HIAA and Dopac normally large increase in circulating FAs that is seen during sub-
(3,4-dihydroxyphenylacetic acid). In the 1-h group, 5-HT and 5- maximal exercise is at least partially blocked by CHO ingestion
HIAA concentrations were increased in all brain regions except (17). Because FAs have a higher affinity for albumin than do the
the hippocampus, where only 5-HIAA was elevated. In the loosely bound TRP, this would attenuate the normal large by guest on October 3, 2012
fatigue group, 5-HT was similarly elevated in all brain regions, increase in f-TRP and f-TRP-to-BCAA ratio that is expected dur-
but 5-HIAA was further increased in the striatum and the mid- ing prolonged exercise (Figure 2). Unlike the situation during
brain. Interestingly, dopamine and Dopac both increased at 1 h rest, in which a high-CHO meal would elicit a large increase in
but had returned to control amounts after fatigue. These results plasma insulin and a corresponding decrease in BCAA concen-
indicate that 5-HT and 5-HIAA concentrations increase during trations (9, 14), the insulin response is blunted during exercise to
endurance exercise and are highest at fatigue. the extent that little or no decrease in plasma BCAA occurs (17).
The aforementioned studies provide good evidence of increased Blomstrand et al (31, 32) have focused on the administration
5-HT and 5-HIAA concentrations in whole brain tissue at spe- of BCAAs as a means of delaying central fatigue during pro-
cific time points during prolonged exercise. However, these stud- longed activities, such as marathon racing, cross-country ski rac-
ies do not differentiate between intra- and extracellular concen- ing, and soccer matches. When 7.5–21 g of BCAAs were admin-
trations, which is necessary to determine whether the changes istered before and during exercise, small improvements were
are due to the release of 5-HT from the serotonergic neuron ter- reported in both physical (31) and mental (32) performance in
minals. Techniques involving in vivo microdialysis have been some subjects. It should be noted, however, that although field
used to examine this issue and support the conclusion that studies such as these are designed to mimic the real-world situa-
increased release of 5-HT occurs in various regions of the brain tions of athletes, such studies are often limited in scientific
(25, 26). However, no such studies have been conducted during value. For example, subjects are often not appropriately matched
fatiguing exercise. Further development of this technique should to prevent inherent differences in the performance capacities of
provide exciting new avenues for exploration of central fatigue the groups before being assigned to control and experimental
in the exercise model. groups. In addition, studies of this nature often do not, or cannot,
A better cause and effect relationship between increased brain blind subjects to experimental treatments to prevent bias on the
5-HT and fatigue was demonstrated in a series of experiments part of the subjects toward the treatment that they believe to be
involving pharmacologic alterations in brain 5-HT activity dur- better. Finally, these studies often fail to control important vari-
ing exercise in rats (19, 27). We proposed that if 5-HT could be ables, ie, exercise intensity and food and water intake, across the
artificially increased through the administration of 5-HT ago- treatment groups. These and other limitations increase the likeli-
nists (drugs that specifically increase 5-HT activity), fatigue hood that the benefits ascribed to a particular nutritional supple-
would occur earlier. In contrast, if 5-HT antagonists (drugs that ment may have actually resulted from inherent differences in the
decrease brain 5-HT activity) were administered, fatigue would groups, subject bias, or uncontrolled variables.
be delayed. The experiments demonstrated that run time to In well-controlled laboratory experiments, the administration
exhaustion decreased after the administration of specific 5-HT of BCAA showed to have no benefits on performance during
576S DAVIS ET AL
to fatigue. Ten endurance-trained athletes randomly completed a
session of cycle ergometry exercise to fatigue at 70–75% of their
maximal power output after being given (a) low concentrations
–1
of BCAA (6 g/L ) in 6% CHO, (b) high concentrations of
–1 –1
BCAA (18 g/L ) in 6% CHO, or (c) TRP (36 g/L ) in a 6%
CHO solution. Despite large changes in plasma concentrations
of BCAA and total TRP, exercise time to exhaustion (≈122 min)
was not different among treatments. The authors concluded that
these manipulations either had no additional effect on serotoner-
gic activity in the brain or that manipulation of serotonergic
activity functionally does not contribute to mechanisms of
fatigue. This brings up an important issue regarding the pre-
sumed effect of supplementation on brain neurochemistry, which
of course cannot be directly assessed in human studies.
We completed a pilot study in rats that addresses this issue
in part (37). We tested the effects of BCAA or CHO feedings
on 5-HT and 5-HIAA concentrations in the midbrain and stria-
tum after 60, 90, and 120 min of treadmill running. No con-
centration differences were found in either brain region at 60
and 90 min. At 120 min, however, 5-HT and 5-HIAA concen-
trations were lower in the brainstem in both the BCAA and the Downloaded from
CHO groups than in a water-fed group. 5-HT concentrations in
the striatum were also lower in the CHO group at 120 min.
Whether these changes reflect differences in central fatigue
awaits further study.
For BCAAs to be physiologically effective in reducing central
fatigue, large doses are probably required. Large doses, however, ajcn.nutrition.org
are likely to increase the ammonia concentration in plasma,
which is known to be toxic to the brain and muscle (36). It has
been suggested that buffering of ammonia could lead to early
fatigue in working muscles by depleting glycolytically derived
carbon skeletons (pyruvate) and draining intermediates of the tri- by guest on October 3, 2012
carboxylic acid cycle (38). Large doses of BCAA during exer-
FIGURE 2. Proposed effects of carbohydrate (CHO) and branched cise are also likely to slow water absorption across the gut, cause
chain amino acids (BCAA) on central fatigue during prolonged exercise. gastrointestinal disturbances, and decrease fluid palatability.
FA, fatty acid; f-TRP, free tryptophan; 5-HT, 5-hydroxytryptamine To assess the effects of a smaller, more palatable supplement
(serotonin); TRP, tryptophan. of BCAAs (0.5 g h–1 BCAA consumed in a CHO-electrolyte
drink), we studied the effects of supplementation on cycling per-
·
formance to fatigue at 70% VO2 max (39). This low dose of
prolonged bouts of exercise. Using a double-blinded, crossover BCAA was chosen to replace the calculated maximum amount of
design, Varnier et al (33) found no differences in performance of BCAA uptake and metabolism by muscle that was likely to occur
a graded incremental exercise test to fatigue after the infusion of under these conditions; and to decrease the likelihood that the
20 g of BCAA or saline over 70 min before exercise. Addi- BCAA supplements would impair water absorption rates in the
tionally, Verger et al (34) reported that fatigue occurred earlier gut, produce gastrointestinal distress, or otherwise be unpalat-
during prolonged treadmill running in rats fed relatively large able. The results of this study showed that the low-dose BCAA
amounts of BCAAs than in those fed either water or glucose. supplement added to a CHO-electrolyte drink was palatable, did
To further assess the potential role of BCAA supplementation not cause gastrointestinal distress, and prevented the slight drop
on exercise performance, Blomstrand et al (35) devised a cycle in BCAA concentration in plasma that occurred during pro-
ergometry protocol for trained athletes in a controlled laboratory longed cycling when subjects consumed the CHO-electrolyte
study. In this study, 5 endurance-trained male cyclists performed drink without the BCAA supplement. However, the added
·
cycle ergometer exercise to fatigue at 75% VO2 peak, preceded BCAAs did not affect ride times to fatigue, perceived exertion,
by a glycogen-reducing activity. On separate occasions, subjects or various measures of cardiovascular and metabolic function.
–1 It seems reasonably clear from the weight of the evidence in
were randomly given (a) BCAA (7 g/L ) in a 6% CHO solution,
(b) 6% CHO solution, or (c) flavored water placebo. Increases in the literature that BCAA supplementation is probably not an
performance were seen in subjects given CHO and in those given appropriate nutritional strategy for delaying central fatigue and
BCAA in CHO solution as compared with those given placebo. enhancing performance. On the other hand, the literature is con-
Results further indicated no additional benefits of the added sistent in showing beneficial effects of CHO feedings during
BCAA despite increases in BCAA concentrations in plasma prolonged exercise when compared with a water placebo. This is
(120%) and muscle (35%). not surprising, given the well-known benefit of CHO feedings on
In another well-controlled study, van Hall et al (36) tested the muscle metabolism and fatigue. It is also possible, however, that
effects of both TRP and BCAA supplementation on cycling time CHO feedings can delay central fatigue. Therefore, a more
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